The ability of rhIFNalpha to enhance the efficacy of MRK-16 (an anti-P- 170 monoclonal antibody [mAb]) to reverse vincristine (VCR) resistance in Ht-29Mdr1 xenografts was investigated. Treatment of mice with MRK-16 (500fgs) prior to exposure to VCR (1mg/kg) weekly for three weeks beginning 10 days post-tumor cell injection resulted in a significant increase in MST (79 days, p < .0001) when compared to the untreated control group (MST=47 days). Furthermore, coadministration of IFNalpha (5 X 10,000 units) and MRK-16 at a similar regimen further enhanced the antitumor activity of VCR (MST=120 days, p < .0001). As another approach to circumvention of drug resistance, it was observed that Ht- 29Mdr1 cells treated with a specific immunotoxin (IT), MRK-16/CRM107, resulted in inhibition of protein synthesis in a dose-dependent manner. In additional studies, cohorts of mice that received intracavity treatment beginning 10 days post OVCAR-3 injection with 10fg 454A12/rRTA alone or concomitantly with rhIFN (5 x 10,000 units) exhibited a significantly increased MST of 89 (10% long-term survivors), and >120 days (70% long-term survivors), respectively (p < .0001) when compared to the control group (41 days). The ip injection of the IT alone or in combination with rhIFNalpha administered by an identical regimen beginning 15 days post-tumor cell injection resulted in significantly (p < .0001) increased MSTs of 72 and 75 days, respectively. No long-term survivors were observed. Multiple treatments of 454A12/rRTA (10microg) following cytoreductive therapy (cytoxan/cis-platin) resulted in a MST of 129 days. Under these conditions, coadministration of rhIFNalpha with 454A12/rRTA resulted in an enhanced therapeutic response (MST=162 days, p=0.0037 between survival curves). A novel IT, HB21 F(Ab')2/VA) was found to be comparable in vitro to the antitumor activity of 454A12/rRTA. Such a construct is now being tested for antitumor effects in vivo.